1. Field of the Invention
This invention relates to a biochip reader of a DNA chip, a protein chip, etc., and in particular to a biochip reader that can flexibly deal with performance variations of an optical system and secular changes in an optical system and makes it possible to reduce costs.
2. Description of the Related Art
A biochip has a substrate on which several thousand to several ten thousand types of pieces of already known DNA are placed like an array. Using the nature of binding DNA pieces of the same type if a piece of unknown DNA is allowed to flow into such a DNA chip, already known DNA bound is examined using a biochip reader, thereby determining an unknown DNA sequence, etc.
FIG. 17 is a schematic representation to show an example of hybridization on such a biochip. In FIG. 17, sites of six types of DNA pieces indicated by “DN01,” “DN02,” “DN03,” “DN04,” “DN05,” and “DN06” are placed as an array on a substrate indicated by “SB01”, making up a DNA chip.
On the other hand, “UN01” in FIG. 17 is an unknown DNA piece to which a fluorescent mark is previously added as indicated by “LM01” in FIG. 17. Such an unknown DNA piece is hybridized with the above-described DNA chip, whereby the DNA pieces with complementary sequences are bound.
For example, the unknown DNA piece of “UN01” in FIG. 17 is bound with the already known DNA piece of “DN01” in FIG. 17 as “CB01” in FIG. 17.
Using the biochip reader, excitation light is applied to the DNA chip thus hybridized and fluorescence occurring on the fluorescent mark is detected, whereby which piece of already known DNA the unknown DNA piece is bound with can be determined.
For example, fluorescence occurs only in the portion where “CB01” occurs in FIG. 17 in the image of the scanning result of the DNA chip as indicated by “SI01” in FIG. 17 and therefore fluorescence is detected only from the portion indicated by “LD01” in FIG. 17.
JP-A-2001-194309, JP-A-2001-194310, JP-A-2003-028799, JP-A-2003-057557 and JP-A-2004-138420 are referred to as related art relevant to a biochip reader such as a DNA chip or a protein chip.
FIG. 18 is a block diagram to show a configuration example of a biochip reader in a related art. In FIG. 18, numeral 1 denotes a microlens plate formed with a plurality of microlenses on a circular substrate, numeral 2 denotes a dichroic mirror for transmitting or reflecting light in response to the wavelength of the light, numeral 3 denotes a biochip having a plurality of sites placed like an array, numeral 4 denotes a lens, numeral 5 denotes a barrier filter for blocking transmission of light in a specific wavelength region, numeral 6 denotes a photographing section such as a camera, and numeral 7 denotes a driving section such as a motor for rotating the microlens plate 1.
Excitation light indicated by “EL11” in FIG. 18, outgoing light from a light source (not shown) such as a laser light source for emitting coherent light, is applied to the microlens plate 1, and the excitation light collected on the microlenses formed on the microlens plate 1 is passed through the dichroic mirror 2 and is collected on the biochip 3.
Fluorescence occurring on the biochip 3 by the excitation light (specifically, fluorescence occurring on the site where a plurality of DNA pieces of the same type are placed) is reflected on the dichroic mirror 2 and the reflected light is passed through the barrier filter 5 by the lens 4 and is collected on the photographing (image capturing) section 6.
On the other hand, the driving section 7 rotates the microlens plate 1 on the center axis of a disk, whereby the positions of the microlenses formed on the microlens plate 1 move and accordingly the excitation light collected on the microlenses scans over the surface of the biochip 3.
For example, FIG. 19 is a plan view to show an example of the microlens plate 1. As shown in FIG. 19, the microlenses are arranged spirally as indicated by “ML21” in FIG. 19 on the microlens plate 1 and the microlens plate 1 thus formed with the microlenses is rotated on the center axis, whereby the excitation light collected on the microlenses scans over the surface of the biochip 3. (A pattern example is described in Japanese Patent Nos. 2663766 and 2692416.)
However, in the related art example shown in FIG. 18, the microlenses are formed at the accurate positions of the microlens plate 1 and the center axis is provided accurately and eccentricity of the motor of the driving section 7, rotation synchronization with the camera of the photographing section 6, etc., is required, thus resulting in an increase in cost; this is a problem.
To use outgoing light of a laser light source as excitation light, performance variations such as light distribution unevenness of the outgoing light of the laser light source or dirt and secular changes (aging) in the optical system of the lens, the dichroic mirror, etc., directly affect the image photographed with the photographing section 6, worsening S/N; this is a problem
For example, FIGS. 20 and 21 are schematic representations to show examples of a photograph image and the distribution characteristic of any axial light amounts when a fluorescent plate for uniformly producing fluorescence in response to excitation light is used instead of the biochip 3.
As shown in FIG. 20, patterns like unevenness and interference fringes caused by performance variations such as light distribution unevenness of the outgoing light of the laser light source or dirt and secular changes in the optical system are reflected on the photograph image although it should be an image with uniform light amount, and it is easily seen that the characteristic curve of light amounts is not uniform light amount and S/N worsens in “CH41” in FIG. 21 indicating the light quantity distribution on the line indicated by “LN31” in FIG. 20.
The reason is that interference noise such as speckle noise easily occurs because coherent light of a laser, etc., is used as the light source.